KR0157422B1 - Process for production of 6-(3-dimethylamino-propionyl)forskolin - Google Patents

Process for production of 6-(3-dimethylamino-propionyl)forskolin

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KR0157422B1
KR0157422B1 KR1019910019298A KR910019298A KR0157422B1 KR 0157422 B1 KR0157422 B1 KR 0157422B1 KR 1019910019298 A KR1019910019298 A KR 1019910019298A KR 910019298 A KR910019298 A KR 910019298A KR 0157422 B1 KR0157422 B1 KR 0157422B1
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formula
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dimethylaminopropionyl
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acetyl
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KR920009841A (en
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아끼히로 마시바
유다까 오가와
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다께다 가즈히꼬
닛뽕가야꾸 가부시기가이샤
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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Abstract

Disclosed in a process for producing 6-(3-dimethylaminopropionyl)forskolin, comprising the sequential steps of: (1) acetylating hydroxy groups in the 1-position and 7-position of a compound represented by the formula (III): <CHEM> to prepare 1-acetyl-6-(3-dimethylaminopropionyl)forskolin represented by the formula (II): <CHEM> (wherein Ac represents acetyl group), and (2) selectively removing the acetyl group in the 1-position of the compound represented by the formula (II) in the presence of an amine represented by the formula (IV): <CHEM> (wherein R1 represents hydrogen atom or lower alkyl group having 1-6 carbon atoms, and R2 represents lower alkyl group having 1-6 carbon atoms, alkoxyalkyl group, aminoalkyl group or benzyl group) in a solvent to prepare 6-(3-dimethylaminopropionyl)forskolin represented by the formula (I): <CHEM> (wherein Ac represents the same as defined in the formula (II)). The compound (I) is promising as a therapeutic agent for cardiac failure.

Description

6-(3-디메틸아미노프로피오닐)포르스콜린 제조방법6- (3-dimethylaminopropionyl) phospholine preparation method

본 발명은 심기능 부전증 치료제로 기대되는6-(3-디메틸아미노프로피오닐)포르스콜린의 신규 제조방법에 관한 것이다.The present invention relates to a novel method for preparing 6- (3-dimethylaminopropionyl) phospholine, which is expected as a therapeutic agent for heart failure.

아래의 구조식(Ⅲ)으로 나타내어지는 화합물의 1 위치 및 7 위치에 있는 히드록시 그룹을 아세틸화하여 아래의 구조식(Ⅱ)로 나타내어지는 화합물을 제조한 다음 구조식(Ⅱ)의 화합물의 1 위치에 있는 아세틸 그룹을 선택적으로 제거하여 아래의 구조식(Ⅰ)으로 나타내어지는 6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하는 방법은 이미 공지되어 있다.(EP-0297496-A2)By acetylating the hydroxy groups at the 1 and 7 positions of the compound represented by the following structural formula (III), a compound represented by the following structural formula (II) was prepared and then at the 1 position of the compound of the structural formula (II) A method for producing 6- (3-dimethylaminopropionyl) phospholine represented by Structural Formula (I) below by selectively removing an acetyl group is already known. (EP-0297496-A2)

탈아세틸화제로서 수산화나트륨을 사용하는 위에 나온 EP 특허 명세서에 의하면 구조식(Ⅰ)으로 나타내어지는 화합물의 수율은 구조식(Ⅲ)으로 나타내어지는 화합물 중량기준으로 54 wt.%이므로 이수율을 증대시킬 필요가 있었다.According to the above EP patent specification using sodium hydroxide as the deacetylating agent, the yield of the compound represented by the formula (I) is 54 wt.% Based on the weight of the compound represented by the formula (III). .

본 발명자들은 여러 가지로 연구한 결과 탈아세틸화제로서 구조식(Ⅳ)의 아민을 사용하면 구조식(Ⅰ)의 화합물을 고순도 및 약 90% 정도의 고수율로 제조할 수 있다는 것을 확인하였다.The inventors of the present invention have found that the use of the amine of formula (IV) as a deacetylating agent can produce the compound of formula (I) with high purity and high yield of about 90%.

(위의 식에서 R1은 수소원자 또는 저급( C1-C6)알킬 그룹이고, R2는 저급( C1-C6)알킬 그룹, 알콕시알킬 그룹, 아미노알킬 그룹 또는 벤질 그룹이다)(Wherein R 1 is a hydrogen atom or a lower (C 1 -C 6 ) alkyl group and R 2 is a lower (C 1 -C 6 ) alkyl group, an alkoxyalkyl group, an aminoalkyl group or a benzyl group)

본 발명은 위와같은 발견에 근거를 두어 완성된 것이다.The present invention has been completed based on the above findings.

즉 본 발명은 (a) 구조식(Ⅲ)으로 나타내어지는 화합물의 1 위치와 7 위치에 있는 히드록시 그룹을 아세틸화하여 구조식(Ⅱ)으로 나타내어지는 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하고, (b) 구조식(Ⅱ)의 화합물의 1위치에 있는 아세틸 그룹을 용매중에서 구조식(Ⅳ)으로 나타내어지는 아민존재하에 선택적으로 제거하여 구조식(Ⅰ)으로 나타내어지는 6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하는 순차적인 단계로 되어 있는 6-(3-디메틸아미노프로피오닐)포르스콜린 제조방법을 제공한다.That is, the present invention (a) 1-acetyl-6- (3-dimethylaminopropionyl represented by Structural Formula (II) by acetylating hydroxy groups at positions 1 and 7 of the compound represented by Structural Formula (III) 6) represented by Structural Formula (I) by preparing forscholine and (b) selectively removing the acetyl group at position 1 of the compound of Structural Formula (II) in the presence of an amine represented by Structural Formula (IV) in a solvent Provided is a method for preparing 6- (3-dimethylaminopropionyl) phospholine, which is a sequential step of preparing (3-dimethylaminopropionyl) phospholine.

위의 식들에서 Ac는 아세틸 그룹이고, R1은 수소원자 이거나 탄소원자수 1∼6 의 저급 알킬 그룹이며, R2는 탄소원자수 1∼6 의 저급 알킬 그룹, 알콕시 알킬 그룹, 아미노알킬 그룹 또는 벤질 그룹이다.In the above formula, Ac is an acetyl group, R 1 is a hydrogen atom or a lower alkyl group of 1 to 6 carbon atoms, R 2 is a lower alkyl group of 1 to 6 carbon atoms, an alkoxy alkyl group, an aminoalkyl group or a benzyl group to be.

본 발명의 방법에 의하면 선행기술에 있어서, 생성물이 분해하여 부생물을 형성하는 것을 완전히 방지함으로써, 고수율로 목적하는 바의 생성물인 6-(3-디메틸아미노프로피오닐)포르스콜린을 정량적으로 제조할 수 있다. 따라서, 반응을 시킨후에 칼럼 크로마토그래피와 용매중에서의 재결정 등의 번잡스러운 정제 과정을 필요로 함이 없이 단순한 분리법으로 6-(3-디메틸아미노프로피오닐)포르스콜린을 고수율 및 고순도로 제조할 수 있기 때문에 본 발명의 제조방법은 대규모 합성에 적합하다.According to the method of the present invention, in the prior art, 6- (3-dimethylaminopropionyl) phospholine, which is the desired product in high yield, is completely quantitatively prevented from decomposition of the product to form a by-product. It can manufacture. Therefore, after the reaction, 6- (3-dimethylaminopropionyl) forskolin can be prepared in high yield and high purity by a simple separation method without requiring complicated purification procedures such as column chromatography and recrystallization in a solvent. As such, the process of the present invention is suitable for large scale synthesis.

위에 나온 구조식(Ⅳ) 의 아민에서 R1은 수소원자와 저급 ( C1-C6)알킬 그룹, 예컨대 메틸, 에틸, 프로필, 부틸, 펜틸 및 헥실을 포함한다. R2에 속하는 것으로는 R1에 있어서와 마찬가지의 저급( C1-C6)알킬 그룹, 알콕시 알킬 그룹(예 : 메톡시프로필, 에톡시프로필), 아미노알킬 그룹(예 : 아미노에틸, 메틸아미노프로필 및 디메틸아미노프로필), 페닐 그룹 등이 있다.R 1 in the amine of formula IV above includes a hydrogen atom and a lower (C 1 -C 6 ) alkyl group such as methyl, ethyl, propyl, butyl, pentyl and hexyl. Those belonging to R 2 include the same lower (C 1 -C 6 ) alkyl groups as in R 1 , alkoxy alkyl groups (eg methoxypropyl, ethoxypropyl), aminoalkyl groups (eg aminoethyl, methylamino Propyl and dimethylaminopropyl), phenyl groups and the like.

구조식(Ⅳ)으로 나타내어지는 아민의 예로서는 디메틸아민, 디에틸아민, 디-n-프로필아민, 디이소프로필아민, 디-n-부틸아민, 디이소부틸아민, 메틸아민, 에틸아민, n-프로필아민, 이소프로필아민, n-부틸아민, 이소부틸아민, sec-부틸아민, tert-부틸아민, n-펜틸아민, n-헥실아민, 시클로헥실아민, 3-메톡시프로필아민, 3-에톡시프로필아민, 2-에틸헥실에톡시프로필아민, 에틸렌디아민, 메틸아미노프로필아민, 디메틸아미노프로필아민, 디에틸아미노프로필아민, 벤질아민 등이 있다.Examples of the amine represented by the formula (IV) include dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, methylamine, ethylamine, n-propyl Amine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, n-pentylamine, n-hexylamine, cyclohexylamine, 3-methoxypropylamine, 3-ethoxy Propylamine, 2-ethylhexylethoxypropylamine, ethylenediamine, methylaminopropylamine, dimethylaminopropylamine, diethylaminopropylamine, benzylamine and the like.

이중에서 가장 바람직한 아민은 구조식(Ⅰ) 으로 나타내어지는 화합물의 6 위치에 있는 디메틸아미노프로피오닐 그룹의 디메틸아미노 그룹을 기타 아미노 그룹으로 치환하는 치환반응에 의하여 부생물이 생성되지 않아야 한다는 관점에서 디메틸아민이다.Among them, the most preferred amine is dimethylamine in view of the fact that no by-products are generated by a substitution reaction in which the dimethylamino group of the dimethylaminopropionyl group at the 6-position of the compound represented by the formula (I) is replaced with other amino groups. to be.

본 발명에서 사용되는 아민은 용액 또는 가스상태의 것이다. 아민이 용액상태일 경우에는 물이 용매로서 바람직하다. 구조식(Ⅱ)으로 나타내어지는 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린 또는 구조식(Ⅲ) 으로 나타내어지는 화합물에 대하여 아민 사용량이 0.1 당량 이상 인한에 있어서, 아민 사용량에 어떤 특별한 한정이 있는 것은 아니지만, 그 사용량은 바람직하게는 0.1∼ 20 당량, 보다 바람직하게는 1.0∼ 20 당량이다.The amines used in the present invention are in solution or gaseous state. When the amine is in solution, water is preferred as the solvent. The amount of amine used is not less than 0.1 equivalents relative to 1-acetyl-6- (3-dimethylaminopropionyl) phospholine represented by the formula (II) or the compound represented by the formula (III). Although not limited, the amount thereof is preferably 0.1 to 20 equivalents, more preferably 1.0 to 20 equivalents.

본 발명에 사용되는 반응 용매가 구조식(Ⅱ)으로 나타내어지는 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린을 용해하고 반응에 치명적인 것이 아니며 일반적으로 극성 용매를 사용하는 한에 있어서는 사용되는 반응 용매에 대하여 특성은 없다. 바람직한 용매는 C1-C4유기 극성 용매인데 그 예로서는 알코올류(예 : 메탄올 에탄올 및 프로판올), 케톤류(예 : 아세톤 및 메틸 에틸 케톤), 에스테르류(예 : 메틸 아세테이트 및 에틸 아세테이트), 할로겐화 탄화수소(예 : 메틸렌 클로라이드 및 클로로포름), 디메틸술폭시드, N,N-디메틸포름아미드 및 물과 혼화되는 용매인 경우에 있어서, 위에 나온 각종 용매를 함유하는 함수 용매등이 있다.As long as the reaction solvent used in the present invention dissolves 1-acetyl-6- (3-dimethylaminopropionyl) forskolin represented by the formula (II) and is not fatal to the reaction and generally uses a polar solvent, There is no characteristic with respect to the reaction solvent used. Preferred solvents are C 1 -C 4 organic polar solvents, for example alcohols (e.g. methanol ethanol and propanol), ketones (e.g. acetone and methyl ethyl ketone), esters (e.g. methyl acetate and ethyl acetate), halogenated hydrocarbons (E.g. methylene chloride and chloroform), dimethyl sulfoxide, N, N-dimethylformamide, and a solvent miscible with water, there are water-containing solvents containing the various solvents mentioned above.

함수 용매중에는 물을 바람직하게는 50 v/v% 이하, 보다 바람직하게는 0.5∼40 v/v% 함유한다. 보다 바람직한 함수 용매는 탄소원자수가 1∼ 4이고 물을 0.5∼ 20 v/v% 함유하는 알코올이다.The water-containing solvent preferably contains 50 v / v% or less, more preferably 0.5 to 40 v / v%. More preferable hydrous solvents are alcohols having 1 to 4 carbon atoms and containing 0.5 to 20 v / v% of water.

반응온도는 통상적으로 0℃ ∼ 용매의 비점의 범위인데, 바람직하게는 0℃∼ 80℃, 보다 바람직하게는 15℃∼ 50℃ 이고, 반응을 4∼ 40 시간 이내에 완료시킨다. 반응온도가 낮을때는 반응시간은 길어지는데, 반응도중 반응온도를 올려주어 반응시간을 단축할 수 있다.The reaction temperature is usually in the range of 0 ° C to the boiling point of the solvent, preferably 0 ° C to 80 ° C, more preferably 15 ° C to 50 ° C, and the reaction is completed within 4 to 40 hours. When the reaction temperature is low, the reaction time is long, the reaction time can be shortened by raising the reaction temperature during the reaction.

반응 용매가 물과 혼합되는 용매일때는 반응 종료후에 반응 혼합물에다 용매의 경우와 동일한 량 또는 바람직하게는 40∼ 60 v/v% 함수용매로 될 수 있는 량의 물을 가한 다음 혼합물을 여과함으로써, 반응혼합물로 부터 소요의 생성물을 쉽사리 분리 할 수 있다.When the reaction solvent is a solvent mixed with water, after completion of the reaction, water is added to the reaction mixture in the same amount as that of the solvent, or preferably in an amount of 40 to 60 v / v% water solvent, and then the mixture is filtered. The desired product can be easily separated from the reaction mixture.

반응용매가 물과 혼합되지 않는 용매일때는 반응혼합물에 물을 가하고 수득한 유기상을 분리하여 농축하고, 잔류물에 함수 알코올을 가하여 결정화한 다음 생성된 결정을 여과해서 수거하는 방식으로 분리를 한다. 이 경우에 있어서, 결정을 함수 알코올로 세척하면 훨씬 효과가 있다.When the reaction solvent is a solvent which is not mixed with water, water is added to the reaction mixture, and the obtained organic phase is separated and concentrated, and the residue is crystallized by adding hydrous alcohol, and the resulting crystals are separated by filtration. In this case, washing the crystals with hydrous alcohol is much more effective.

위에 나온 EP-027496-A2 에 기재된 바와같이 화합물(Ⅲ)의 1 위치와 7 위치에 있는 히드록실 그룹을 용매중에서 아세틸화하여 화합물(Ⅱ)을 제조한다. 즉, 구조식(Ⅲ)의 화합물의 아세틸화는 화합물(Ⅲ) 1 몰당 아세틸화제 약 2∼ 약 50 몰, 바람직하게는 약 2∼ 약 4 몰을 사용하여 용매중에서 약 0℃∼ 용매의 비점, 바람직하게는 약 0℃∼ 35℃ 에서 수분∼ 약 24 시간, 바람직하게는 수분∼ 약 2 시간 동안 반응시켜 구조식(Ⅲ)의 화합물을 아세틸화한다. 아세틸화에 사용되는 용매의 예로서는 피리딘, 벤젠, 클로로포름, 에테르, 디클로로메탄, 1,1,1-트리클로로에탄, 1,2-디클로로에탄, 사염화 탄소 및 에틸 아세테이트가 있는데, 이중에서 바람직한 것은 피리딘이다.Compound (II) is prepared by acetylation of the hydroxyl groups at positions 1 and 7 of compound (III) in a solvent as described in EP-027496-A2 above. That is, the acetylation of the compound of formula (III) is carried out at about 0 ° C. to the boiling point of the solvent, preferably from about 2 to about 50 moles, preferably from about 2 to about 4 moles of an acetylating agent per mole of compound (III). Preferably, the compound of formula (III) is acetylated by reacting at about 0 ° C to 35 ° C for several minutes to about 24 hours, preferably for several minutes to about 2 hours. Examples of solvents used for acetylation include pyridine, benzene, chloroform, ether, dichloromethane, 1,1,1-trichloroethane, 1,2-dichloroethane, carbon tetrachloride and ethyl acetate, of which pyridine is preferred. .

아세틸화제의 예로서는 아세트산과 그 반응성 유도체(예 : 아세틸 클로라이드, 아세틸 브로마이드 등의 아세틸 할라이드), 아세트산 무수물등이 있다. 이 반응에 있어서, 반응온도를 높게 하지 않고서도 반응이 원만하게 진행되기 때문에 4-디메틸아미노피리딘 촉매량을 사용하는 것이 바람직하다.Examples of acetylating agents include acetic acid and its reactive derivatives (such as acetyl halides such as acetyl chloride, acetyl bromide), acetic anhydride and the like. In this reaction, since the reaction proceeds smoothly without increasing the reaction temperature, it is preferable to use a 4-dimethylaminopyridine catalytic amount.

위의 아세틸화 반응에서 수득한 화합물(Ⅱ)을 용매를 증류한 후에 사용한다. 이와같이 해서 수득한 조생성물(組生成物) 그 자체를 다음에 나오는 선택적인 탈아세틸화 반응에 사용할 수도 있겠으나, 바람직한 것은 아세트산 같은 산 성분을 조생성물로 부터 제거하는 것이다. 산 성분을 제거하자면 예컨대 암모니아 등과 같은 알칼리를 함유한 물과 혼화되지 아니하는 유기용매중에 조생성물을 용해시킨 다음 여기에 물을 가하여 산 성분을 물로 추출하는 방법을 사용한다.Compound (II) obtained in the above acetylation reaction is used after distilling off the solvent. The crude product thus obtained may also be used for the subsequent selective deacetylation reaction, but the preferred is to remove acid components such as acetic acid from the crude product. To remove the acid component, for example, a crude product is dissolved in an organic solvent which is not mixed with alkali-containing water such as ammonia, and then water is added to extract the acid component.

본 발명을 실시예에 따라 구체적으로 설명한다.The present invention will be described in detail by way of examples.

[실 시 예 1][Example 1]

(1-1) : 7-데아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린 10.0g(21.38 mmol), 4-디메틸아미오피리딘 7.0 mg 및 피리딘 30㎖으로 된 혼합용액에다 아세트산 무수물 6.55 g(64.14 mmol)을 빙냉하에 가하고 20℃ 에서 5 시간 반응시킨 다음 메탄올 3 ㎖ 을 반응 혼합물에 가한후 혼합물을 감압하에 농축하여 용매를 제거하였다.(1-1): Acetic anhydride in a mixed solution of 7-deacetyl-6- (3-dimethylaminopropionyl) phospholine 10.0 g (21.38 mmol), 7.0 mg of 4-dimethylamiopyridine and 30 ml of pyridine 6.55 g (64.14 mmol) was added under ice-cooling, the reaction was carried out at 20 ° C. for 5 hours, and then 3 ml of methanol was added to the reaction mixture, and the mixture was concentrated under reduced pressure to remove the solvent.

수득한 잔류물에 에틸 아세테이트 80 ㎖, 진한 암모니아수 8 g 및 10% 소금물 20㎖ 을 가한후 이 혼합물을 교반한 다음 방치하여 생성된 유기상을 분리하였다. 이 유기상을 10% 소금물 20㎖ 로 2회 세척한 다음 무수황산 마그네슘에서 건조시켰다. 수득한 고체 물질을 여과하여 제거하고 여액을 감압하에 농축하여 기름상태의 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린을 얻었다.80 ml of ethyl acetate, 8 g of concentrated ammonia water and 20 ml of 10% brine were added to the residue, and the mixture was stirred and left to separate the resulting organic phase. The organic phase was washed twice with 20 ml of 10% brine and then dried over anhydrous magnesium sulfate. The obtained solid material was filtered off and the filtrate was concentrated under reduced pressure to give oily 1-acetyl-6- (3-dimethylaminopropionyl) phospholine.

(1-2) : 잔류물에 메탄올 30㎖ 와 디메틸아민 50 % 수용액 3.9 g (42.76 mmol)을 가하고 실온에서 20 시간 반응시켰다. 반응이 종료한 후 반응 혼합물에 물 30 ㎖ 을 가하여 결정을 침전시켰다.(1-2): 30 ml of methanol and 3.9 g (42.76 mmol) of 50% aqueous dimethylamine solution were added to the residue, followed by reaction at room temperature for 20 hours. After the reaction was completed, 30 ml of water was added to the reaction mixture to precipitate crystals.

결정을 여과하여 수거해서 50 % 메탄올 10㎖ 로 세척한 다음 건조시켜 6-(3-디메틸아미노프로피오닐)포르스콜린 9.8 g [7-데아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린에 대하여 90 %의 수율]을 얻었다.The crystals were collected by filtration, washed with 10 ml of 50% methanol and dried to 9.8 g of 6- (3-dimethylaminopropionyl) phospholine [7-deacetyl-6- (3-dimethylaminopropionyl) force 90% yield against choline].

이 생성물의 NMR 및 IR 스펙트럼은 별도로 제조한 표준시료의 것과 완전히 일치하였다.The NMR and IR spectra of this product were in full agreement with those of a standard sample prepared separately.

부수적으로 실시예 1-2 의 디메틸아민 대신 메틸아민, 에틸렌디아민, 3-메톡시프로필아민 또는 벤질아민을 사용하여 화합물(Ⅰ)을 제조할 수도 있다.Incidentally, compound (I) may be prepared using methylamine, ethylenediamine, 3-methoxypropylamine or benzylamine instead of the dimethylamine of Example 1-2.

[실 시 예 2][Example 2]

실시예 1-1의 방법과 마찬가지 방법으로 제조한 기름상태의 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린에다 메탄올 30 ㎖, 물 20 ㎖ 및 디메틸아민 50 % 수용액 7.8g (85.5 mmol) 을 가한 다음 40∼ 45℃ 에서 5 시간 반응시켰다.7.8 g of aqueous 1-acetyl-6- (3-dimethylaminopropionyl) phospholine to methanol prepared in the same manner as in Example 1-1 to 30 ml of methanol, 20 ml of water and 50% aqueous dimethylamine solution ( 85.5 mmol) was added and then reacted at 40 to 45 ° C for 5 hours.

반응이 종료한 후 반응 혼합물을 실온까지 냉각하고 침전된 결정을 여과하여 수거한 다음 50 % 메탄올 10 ㎖ 로 세척한 후 건조시켜 6-(3-디메틸아미노프로피오닐)포르스콜린 9.9g [7- 데아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린에 대하여 91 % 의 수율]을 얻었다.After the reaction was completed, the reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration, washed with 10 ml of 50% methanol, and dried to 9.9 g of 6- (3-dimethylaminopropionyl) phospholine [7- 91% yield relative to deacetyl-6- (3-dimethylaminopropionyl) phospholine].

이 생성물의 NMR 및 IR 스펙트럼은 별도로 제조한 표준시료의 것과 완전히 일치하였다.The NMR and IR spectra of this product were in full agreement with those of a standard sample prepared separately.

[실 시 예 3][Example 3]

실시예 1-1의 방법과 마찬가지 방법으로 제조한 기름상태의 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린에다 에틸 아세테이트 30 ㎖ 와 디메틸아민 50 % 수용액 29g (0.32mmol) 을 가한 다음 실온에서 24 시간 반응시켰다.30 ml of ethyl acetate and 29 g (0.32 mmol) of 50% aqueous dimethylamine were added to an oily 1-acetyl-6- (3-dimethylaminopropionyl) phospholine prepared in the same manner as in Example 1-1. After the addition, the mixture was allowed to react at room temperature for 24 hours.

반응이 종료한 후 감압하에 용매를 증류하여 제거하고 잔류물에다 에탈아세테이트 38 ㎖와 물10 ㎖을 가한 다음 이 혼합물을 교반하고 나서 방치하여 형성된 유기상을 분리하였다.After the reaction was completed, the solvent was distilled off under reduced pressure, and 38 ml of ethanol and 10 ml of water were added to the residue, and the mixture was stirred.

유기상을 무수황산 마그네슘에서 건조시킨 후 고체물질을 여과하여 제거하고 여액을 감압하에 농축하고 증발시켰다.The organic phase was dried over anhydrous magnesium sulfate, the solid was filtered off and the filtrate was concentrated under reduced pressure and evaporated.

수득한 잔류물에 메탄올 30 ㎖ 와 물 30 ㎖ 을 가하여 결정화하고 생성된 결정을 여과하여 수거한 다음 물 20 ㎖ 로 세척하고 나서 건조시켜 6-(3-디메틸아미노프로피오닐)포르스콜린 9.6g [7- 데아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린에 대하여 88 % 의 수율]을 얻었다.30 ml of methanol and 30 ml of water were added to the obtained residue to crystallize. The resulting crystals were collected by filtration, washed with 20 ml of water and dried to give 9.6 g of 6- (3-dimethylaminopropionyl) phospholine. 88% yield relative to 7-deacetyl-6- (3-dimethylaminopropionyl) phospholine] was obtained.

이 생성물의 NMR 및 IR 스펙트럼은 별도로 제조한 표준시료의 것과 완전히 일치하였다.The NMR and IR spectra of this product were in full agreement with those of a standard sample prepared separately.

다음에 나오는 것은 화합물(Ⅲ) 의 아실화 반응의 다른 실시예이다.The following is another example of the acylation reaction of compound (III).

7- 데아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린 12g, 4- 디메틸아미노피리딘 35 ㎎, 무수피리딘 48 ㎖ 및 아세트산 무수물 5.9 ㎖ 로 된 혼합물을 실온에서 2 시간 교반한 다음, 4- 디메틸아미노피리딘 35 ㎎ 을 가하였다. 이 혼합물을 다시 3 시간 교반하고 반응이 종료한 후 반응 혼합물에 메탄올 5 ㎖ 을 가한 다음 농축하였다.A mixture of 12 g of 7-deacetyl-6- (3-dimethylaminopropionyl) phospholine, 35 mg of 4-dimethylaminopyridine, 48 ml of anhydrous pyridine and 5.9 ml of acetic anhydride was stirred at room temperature for 2 hours, and then 4 35 mg of dimethylaminopyridine was added. The mixture was stirred for 3 hours again, and after the reaction was completed, 5 ml of methanol was added to the reaction mixture, and the mixture was concentrated.

Claims (7)

(a) 구조식(Ⅲ)으로 나타내어지는 화합물의 1 위치와 7 위치에 있는 히드록시 그룹을 아세틸화하여 구조식(Ⅱ)으로 나타내어지는 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하고, (b) 구조식(Ⅱ)의 화합물의 1위치에 있는 아세틸 그룹을 용매중에서 구조식(Ⅳ)으로 나타내어지는 아민 존재하에 선택적으로 제거하여 구조식(Ⅰ)으로 나타내어지는 6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하는 순차적인 단계로 되어 있는 6-(3-디메틸아미노프로피오닐)포르스콜린 제조방법(a) 1-acetyl-6- (3-dimethylaminopropionyl) forskolin represented by structural formula (II) by acetylating the hydroxy groups at positions 1 and 7 of the compound represented by structural formula (III) (B) 6- (3-dimethyl represented by formula (I) by selectively removing acetyl group at the 1-position of the compound of formula (II) in the presence of an amine represented by formula (IV) in a solvent. Process for preparing 6- (3-dimethylaminopropionyl) phospholine in sequential steps to prepare aminopropionyl) phospholine 위의 식들에 있어서, Ac는 아세틸 그룹이고, R1은 수소원자 이거나 탄소원자수 1∼6 의 저급 알킬 그룹이며, R2는 탄소원자수 1∼6 의 저급 알킬 그룹, 알콕시 알킬 그룹, 아미노알킬 그룹 또는 벤질 그룹이다.In the above formula, Ac is an acetyl group, R 1 is a hydrogen atom or a lower alkyl group of 1 to 6 carbon atoms, R 2 is a lower alkyl group of 1 to 6 carbon atoms, an alkoxy alkyl group, an aminoalkyl group or Benzyl group. 제1항에 있어서, 구조식(Ⅳ) 으로 나타내어지는 아민이 디메틸아민인 제조방법.The process according to claim 1, wherein the amine represented by the formula (IV) is dimethylamine. 제1항 또는 제2항에 있어서, 구조식(Ⅳ) 으로 나타내어지는 아민을 구조식(Ⅱ) 으로 나타내어지는 화합물에 대하여 0.1∼ 20 당량의 양으로 사용하는 제조방법.The production method according to claim 1 or 2, wherein the amine represented by formula (IV) is used in an amount of 0.1 to 20 equivalents based on the compound represented by formula (II). 제1항 또는 제2항에 있어서, 용매가 알코올 또는 에스테르인 제조방법.The process according to claim 1 or 2, wherein the solvent is an alcohol or an ester. 제1항 또는 제2항에 있어서, 용매가 메탄올인 제조방법.The process according to claim 1 or 2, wherein the solvent is methanol. 제1항 또는 제2항에 있어서, (b) 단계에서 아세틸 그룹을 0℃∼ 80℃ 에서 제거하는 제조방법.The process according to claim 1 or 2, wherein the acetyl group is removed at 0 ° C to 80 ° C in step (b). (a) 피리딘중에서 4-디메틸아미노피리딘 존재하에 구조식(Ⅲ) 으로 나타내어지는 화합물을 구조식(Ⅲ) 으로 나타내어지는 화합물 1 몰당 2∼ 8 몰의 아세틸화제로 처리하여 구조식(Ⅱ) 으로 나타내어지는 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하고, (b) 메탄올중에서 구조식(Ⅲ) 으로 나타내어지는 화합물 1 몰당 0.1∼ 20 몰의 디메틸아민 존재하에 구조식(Ⅱ) 으로 나타내어지는 화합물의 1 위치에 있는 아세틸 그룹을 제거하여 구조식(Ⅰ) 으로 나타내어지는 6-(3-디메틸아미노프로피오닐)포르스콜린을 제조하는 순차적인 단계로 되어 있는 6-(3-디메틸아미노프로피오닐)포르스콜린 제조방법.(a) In the pyridine, the compound represented by formula (III) in the presence of 4-dimethylaminopyridine is treated with 2 to 8 moles of an acetylating agent per mole of the compound represented by formula (III) to give 1- Acetyl-6- (3-dimethylaminopropionyl) phospholine was prepared and (b) represented by structural formula (II) in the presence of 0.1 to 20 moles of dimethylamine per mole of compound represented by structural formula (III) in methanol. 6- (3-dimethylaminopropionyl), which is a sequential step of removing the acetyl group at position 1 of the compound to produce 6- (3-dimethylaminopropionyl) forskolin represented by formula (I). Forskolin preparation method. 위의 식들에 있어서 Ac는 아세틸 그룹이다.Ac is an acetyl group in the above formulas. 8. 구족식(Ⅱ) 으로 나타내어지는 1-아세틸-6-(3-디메틸아미노프로피오닐)포르스콜린의 1 위치에 있는 아세틸 그룹 용매중에서 디메틸아민 존재하에 제거하는 단계를 포함하는 구조식(Ⅰ) 으로 나타내어지는 6-(3-디메틸아미노프로피오닐)포르스콜린 제조방법.8. Structural formula (I) comprising the step of removing in the presence of dimethylamine in an acetyl group solvent at position 1 of 1-acetyl-6- (3-dimethylaminopropionyl) forskolin represented by group formula (II) 6- (3-dimethylaminopropionyl) phospholine production method represented by. 위의 식에서 Ac는 아세틸 그룹이다.Ac is an acetyl group in the above formula.
KR1019910019298A 1990-11-01 1991-10-30 Process for production of 6-(3-dimethylamino-propionyl)forskolin KR0157422B1 (en)

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